Ipilimumab在恶性黑色素瘤免疫治疗中的进展_West China Medical Journal

Authors：

李丹丹 ,  刘磊

Corresponding author：

刘磊, Email: antree1100@126.com

Keywords：

恶性黑色素瘤; ipilimumab; 溶解性T细胞相关抗原

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ipilimumab是溶解性T细胞相关抗原（CTLA-4）的单克隆抗体。其作用机制为中和CTLA-4的免疫抑制作用，从而激发机体的抗肿瘤免疫反应。在多中心的Ⅲ期临床试验中，ipilimumab在延长患者生命方面取得了新的进展，因而美国食品药品管理局（FDA）批准ipilimumab用于治疗晚期恶性黑色素瘤患者，是恶性黑色素瘤免疫治疗的重要进步。

Citation： 李丹丹,刘磊. Ipilimumab在恶性黑色素瘤免疫治疗中的进展. West China Medical Journal, 2012, 27(4): 608-612. doi: Copy

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2.	Hünig T, Dennehy K. CD28 superagonists: mode of action and therapeutic potential[J]. Immunol Lett, 2005, 100(1): 21-28.
3.	Thompson CB, Allison JP. The emerging role of CTLA-4 as an immune attenuator[J]. Immunity, 1997, 7(4): 445-450.
4.	Kirkwood JM, Tarhini AA, Panelli MC, et al. Next Generation of immunotherapy for melanoma[J]. J Clin Oncol, 2008, 26(20): 3445-3455.
5.	Perez VL, Van Parijs L, Biuckians A, et al. Induction of peripheral T cell tolerance in vivo requires CTLA-4 engagement[J]. Immunity, 1997, 6(4): 411-417.
6.	Waterhouse P, Penninger JM, Timms E, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4[J]. Science, 1995, 270(5238): 985-985.
7.	Peggs KS, Quezada SA, Allison JP. Cell intrinsic mechanisms of T-cell inhibition and application to cancer therapy[J]. Immunol Rev, 2008, 224(1): 141-165.
8.	Bour-Jordan H, Esensten JH, Martinez-Llordella M, et al. Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28/ B7 family[J]. Immunol Rev, 2011, 241(1): 180-205.
9.	Hodi FS, Mihm MC, Soiffer RJ, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients[J]. Proc Natl Acad Sci USA, 2003, 100(8): 4712-4717.
10.	Hoos A, Ibrahim R, Korman A, et al. Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy[J]. Semin Oncol, 2010, 37(5): 533-546.
11.	Maker AV, Attia P, Rosenberg SA. Analysis of the cellular mechanism of antitumor responses and autoimmunity in patients treated with CTLA-4 blockade[J]. J Immunol, 2005, 175(11): 7746-7754.
12.	Attia P, Phan GQ, Maker AV, et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4[J]. J Clin Oncol, 2005, 23(25): 6043-6053.
13.	Weber JS, O’day S, Urba W, et al. Phase Ⅰ/Ⅱ study of ipilimumab for patients with metastatic melanoma[J]. J Clin Oncol, 2008, 26(36): 5950-5956.
14.	Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study[J]. Lancet Oncol, 2010, 11(2): 155-164.
15.	O’day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase Ⅱ study[J]. Ann Oncol, 2010, 21(8): 1712-1717.
16.	Hersh E, O’day S, Powderly J, et al. A phase Ⅱ multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma[J]. Invest New Drugs, 2011, 29(3): 489-498.
17.	Hodi FS, O’day SJ, Mcdermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma[J]. N Engl J Med, 2010, 363(8): 711-723.
18.	Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma[J]. N Engl J Med, 2011, 364(26): 2517-2526.
19.	Maker AV, Phan GQ, Attia P, et al. Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase Ⅰ/Ⅱ study[J]. Ann Surg Oncol, 2005, 12(12): 1005-1016.
20.	Phan GQ, Yang JC, Sherry RM, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma[J]. Proc Natl Acad Sci USA, 2003, 100(14): 8372-8377.
21.	Weber J, Thompson JA, Hamid O, et al. A randomized, double-blind, placebo-controlled, phase Ⅱ study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage Ⅲ or Ⅳ melanoma[J]. Clin Cancer Res, 2009, 15(17): 5591-5598.
22.	Downey SG, Klapper JA, Smith FO, et al. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade[J]. Clin Cancer Res, 2007, 13(22 Pt 1): 6681-6688.
23.	刘勇, 岑瑛, 许学文, 等. 236例皮肤恶性肿瘤临床分析[J]. 华西医学, 2007, 22(2): 368-369.
24.	Eggermont AM, Kirkwood JM. Re-evaluating the role of dacarbazine in metastatic melanoma: what have we learned in 30 years?[J]. Eur J Cancer, 2004, 40(12): 1825-1836.
25.	刘佳, 周麟, 侯梅. 干扰素α在恶性黑色素瘤术后患者治疗中的研究进展[J]. 华西医学, 2006, 21(2): 429-430.
26.	Thompson JA, Hamid O, Minor D, et al. Ipilimumab in treatment-naive and previously treated patients with metastatic melanoma: retrospective analysis of efficacy and safety data from a phase Ⅱ trial[J]. J Immunother, 2012, 35(1): 73-77.
27.	Small EJ, Tchekmedyian NS, Rini BI, et al. A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer[J]. Clin Cancer Res, 2007, 13(6): 1810-1815.
28.	Lynch TJ, Bondarenko IN, Luft A, et al. Phase Ⅱ trial of ipilimumab (IPI) and paclitaxel/carboplatin (P/C) in first-line stage Ⅲb/Ⅳ non-small cell lung cancer (NSCLC)[J]. J Clin Oncol, 2010, 28(15s): 7531.
29.	Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation[J]. N Engl J Med, 2011, 364(26): 2507-2516.
30.	Comin-Anduix B, Chodon T, Sazegar H, et al. The oncogenic BRAF kinase inhibitor PLX4032/RG7204 does not affect the viability or function of human lymphocytes across a wide range of concentrations[J]. Clin Cancer Res, 2010, 16(24): 6040-6048.
31.	Ku GY, Yuan J, Page DB, et al. Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting[J]. Cancer, 2010, 116(7): 1767-1775.

1. 　Lens MB, Dawes M. Global perspectives of contemporary epidemiological trends of cutaneous malignant melanoma[J]. Br J Dermatol, 2004, 150(2): 179-185.
2. 　Hünig T, Dennehy K. CD28 superagonists: mode of action and therapeutic potential[J]. Immunol Lett, 2005, 100(1): 21-28.
3. 　Thompson CB, Allison JP. The emerging role of CTLA-4 as an immune attenuator[J]. Immunity, 1997, 7(4): 445-450.
4. 　Kirkwood JM, Tarhini AA, Panelli MC, et al. Next Generation of immunotherapy for melanoma[J]. J Clin Oncol, 2008, 26(20): 3445-3455.
5. 　Perez VL, Van Parijs L, Biuckians A, et al. Induction of peripheral T cell tolerance in vivo requires CTLA-4 engagement[J]. Immunity, 1997, 6(4): 411-417.
6. 　Waterhouse P, Penninger JM, Timms E, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4[J]. Science, 1995, 270(5238): 985-985.
7. 　Peggs KS, Quezada SA, Allison JP. Cell intrinsic mechanisms of T-cell inhibition and application to cancer therapy[J]. Immunol Rev, 2008, 224(1): 141-165.
8. 　Bour-Jordan H, Esensten JH, Martinez-Llordella M, et al. Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28/ B7 family[J]. Immunol Rev, 2011, 241(1): 180-205.
9. 　Hodi FS, Mihm MC, Soiffer RJ, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients[J]. Proc Natl Acad Sci USA, 2003, 100(8): 4712-4717.
10. 　Hoos A, Ibrahim R, Korman A, et al. Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy[J]. Semin Oncol, 2010, 37(5): 533-546.
11. 　Maker AV, Attia P, Rosenberg SA. Analysis of the cellular mechanism of antitumor responses and autoimmunity in patients treated with CTLA-4 blockade[J]. J Immunol, 2005, 175(11): 7746-7754.
12. 　Attia P, Phan GQ, Maker AV, et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4[J]. J Clin Oncol, 2005, 23(25): 6043-6053.
13. 　Weber JS, O’day S, Urba W, et al. Phase Ⅰ/Ⅱ study of ipilimumab for patients with metastatic melanoma[J]. J Clin Oncol, 2008, 26(36): 5950-5956.
14. 　Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study[J]. Lancet Oncol, 2010, 11(2): 155-164.
15. 　O’day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase Ⅱ study[J]. Ann Oncol, 2010, 21(8): 1712-1717.
16. 　Hersh E, O’day S, Powderly J, et al. A phase Ⅱ multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma[J]. Invest New Drugs, 2011, 29(3): 489-498.
17. 　Hodi FS, O’day SJ, Mcdermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma[J]. N Engl J Med, 2010, 363(8): 711-723.
18. 　Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma[J]. N Engl J Med, 2011, 364(26): 2517-2526.
19. 　Maker AV, Phan GQ, Attia P, et al. Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase Ⅰ/Ⅱ study[J]. Ann Surg Oncol, 2005, 12(12): 1005-1016.
20. 　Phan GQ, Yang JC, Sherry RM, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma[J]. Proc Natl Acad Sci USA, 2003, 100(14): 8372-8377.
21. 　Weber J, Thompson JA, Hamid O, et al. A randomized, double-blind, placebo-controlled, phase Ⅱ study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage Ⅲ or Ⅳ melanoma[J]. Clin Cancer Res, 2009, 15(17): 5591-5598.
22. 　Downey SG, Klapper JA, Smith FO, et al. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade[J]. Clin Cancer Res, 2007, 13(22 Pt 1): 6681-6688.
23. 　刘勇, 岑瑛, 许学文, 等. 236例皮肤恶性肿瘤临床分析[J]. 华西医学, 2007, 22(2): 368-369.
24. 　Eggermont AM, Kirkwood JM. Re-evaluating the role of dacarbazine in metastatic melanoma: what have we learned in 30 years?[J]. Eur J Cancer, 2004, 40(12): 1825-1836.
25. 　刘佳, 周麟, 侯梅. 干扰素α在恶性黑色素瘤术后患者治疗中的研究进展[J]. 华西医学, 2006, 21(2): 429-430.
26. 　Thompson JA, Hamid O, Minor D, et al. Ipilimumab in treatment-naive and previously treated patients with metastatic melanoma: retrospective analysis of efficacy and safety data from a phase Ⅱ trial[J]. J Immunother, 2012, 35(1): 73-77.
27. 　Small EJ, Tchekmedyian NS, Rini BI, et al. A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer[J]. Clin Cancer Res, 2007, 13(6): 1810-1815.
28. 　Lynch TJ, Bondarenko IN, Luft A, et al. Phase Ⅱ trial of ipilimumab (IPI) and paclitaxel/carboplatin (P/C) in first-line stage Ⅲb/Ⅳ non-small cell lung cancer (NSCLC)[J]. J Clin Oncol, 2010, 28(15s): 7531.
29. 　Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation[J]. N Engl J Med, 2011, 364(26): 2507-2516.
30. 　Comin-Anduix B, Chodon T, Sazegar H, et al. The oncogenic BRAF kinase inhibitor PLX4032/RG7204 does not affect the viability or function of human lymphocytes across a wide range of concentrations[J]. Clin Cancer Res, 2010, 16(24): 6040-6048.
31. 　Ku GY, Yuan J, Page DB, et al. Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting[J]. Cancer, 2010, 116(7): 1767-1775.

West China Medical Journal

Ipilimumab在恶性黑色素瘤免疫治疗中的进展

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